title: A newly discovered role of transcription factors involved in pancreas development and the pathogenesis of diabetes mellitus.
abstract: The prevalence of diabetes mellitus is increasing worldwide, averaging 5% to 15% in various population groups. Diabetes predisposes to premature morbidity and death. The underlying metabolic cause of diabetes is a failure of the beta-cells of the pancreas to provide insulin in amounts sufficient to meet the body's needs, leading to hyperglycemia. Juvenile (type 1) diabetes results from immune destruction of the beta-cells. Adult onset (type 2) diabetes, which accounts for 90% of all forms of diabetes, is a complex polygenic disease manifested in a dysregulation of insulin secretion. Environmental influences and complex genetic traits contribute to the pathogenesis of both types of diabetes. However, a subpopulation of type 2 diabetes is monogenic and due to inactivating mutations in genes that are critical for normal beta-cell function. Heterozygous carriers of the mutant genes develop early-onset diabetes known as MODY (mature onset diabetes of the young). Notably, three MODY genes encode transcription factors implicated in the regulation of insulin gene transcription: hepatocyte nuclear factors 1 alpha and 4 alpha, and islet duodenum homeobox-1 (IDX-1, also known as IPF-1). The fourth gene encodes glucokinase, the rate-limiting enzyme required for glucose metabolism in beta-cells. Further, an individual born without a pancreas (agenesis) is homozygous for an inactivating mutation of the IDX-1 gene, recapitulating the phenotype of the IDX-1 knockout mouse and demonstrating that expression of IDX-1 is critical for pancreas development. Recently, mouse knockouts of the transcription factors Pax4, Pax6, beta 2/neuroD, and Isl-1 result in severe anomalies in the development of the endocrine pancreas. Gene mutations for these factors are possible candidates for additional MODY genes.
authors.affiliation: Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Boston 02114-2696, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Habener
authors.forename: D A
authors.initials: DA
authors.lastname: Stoffers
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003920:Diabetes Mellitus / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010179:Pancreas / Q000196:embryology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein